Study On The Mechanism Of Energy Metabolism Regulation By Ginsenoside CK Via PPAR? Pathway In Alzheimer's Disease

Objective: A series of reports has revealed that energy metabolism disorders and lack of ATP exert detrimental effects on the pathology of Alzheimer's disease(AD).The ginsenoside compound K(CK),a major intestinal metabolite underlying the pharmacological actions of orally administered ginseng,has an ameliorating effect against AD,but the relevant molecular mechanism remains unclear.In this study,we hypothesized that the improvement of AD brought by CK is mediated by the energy metabolism signaling pathway and tested this hypothesis in In vivo and in vitro experiments.Methods: 1 Protective effect of CK on AD model miceMouse behavior was evaluated by water maze and platform tests.Flow cytometry detected hippocampal apoptosis.Neuronal ultrastructure in the hippocampus was observed by transmission electron microscopy(TEM).Thioflavin-S staining detected senile plaque deposition in the brain.Hippocampal A? and PPAR? expression levels were measured by western blot and immunofluorescence.Functional genes were screened by gene chip technology and gut microbiota,mouse fecal samples were assessed and compared for changes in their gut microbiota abundance and for functional gene verification,and verified in subsequent experiments.Hippocampal ATP was measured using an ATP assay kit.Western blot(WB)was run on the proteins associated with the energy metabolism.2 Protective effect of CK on damaged HT22 cellsHT22 cells were incubated with CK and exposed to A?.Cell viability was analyzed using the MTT assay.Cell growth curves were derived from real-time cell analysis.Apoptosis was determined by flow cytometry,A? localization and expression by immunofluorescence,and ATP content by a specific assay kit.The expression of proteins related to the energy metabolism was analyzed using Western blotting.Results: 1 Protective mechanism of CK on AD model miceCK treatment improved mouse behavior relative to the untreated mouse model but PPAR? inhibitors had the opposite effect.The gene chip assay showed significant differences among treatments in terms of their energy metabolism functional genes.CK treatment attenuated hippocampal apoptosis,downregulated and dispersed A?,upregulated and localized PPAR?,reduced senile plaque deposition in the brain,improved hippocampal neuron ultrastructure,normalized the expression of energy metabolism-related proteins,and increased ATP in the hippocampus.In contrast,GW9662 had the contrary effects.CK also normalized gut microbiota.The status of the expression of functional genes associated with energy metabolism is an important factor in the onset and progression of Alzheimer's disease.2 Protective mechanism of CK on damaged HT22 cellsCK treatment improved cell viability,cell growth,and apoptosis induced by A?,and the cellular localization and expression of A? and PPAR?.Moreover,CK increased ATP content by promoting the activity of glucose transporters(GLUTs).Therefore,the neuroprotective effect of CK against A? injury was mainly realized through the activation of the energy metabolism signaling pathway.Conclusions: CK treatment inhibits neuronal damage caused by A? through the activation of the energy metabolism signaling pathway,delayed the learning and memory impairment caused by SCOP exposure.Thus,CK may be a key bioactive constituent of ginseng with therapeutic efficacy against Alzheimer's disease and could be administered as a preventative or curative treatment for AD.